Multilaminate backing construction

ABSTRACT

A novel backing construction for a transdermal drug delivery system is disclosed. In particular, the invention relates to a system and method for labeling a transdermal drug delivery system, wherein the backing layer contains a writable medium capable of inkless printing.

RELATED APPLICATION

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/407,126, filed on Aug. 30, 2002.

TECHNICAL FIELD

[0002] The present invention relates to a multilaminate backingconstruction for a transdermal drug delivery system. In particular, theinvention relates to a system and method for labeling a transdermal drugdelivery system, wherein the outermost layer of the multilaminatebacking construction contains an embossable and writable material.

BACKGROUND OF THE INVENTION

[0003] The use of microporous materials, including films, in labelapplication for various packaging materials, containers, stationary,blood bags, recording paper, bandages and the like has been described ingreat detail. The following patents U.S. Pat. Nos. 6,255,552; 6,162,858;5,906,830; 5,871,829; 5,583,171; 5,507,525; 5,484,603; 5,314,421;4,751,087; 4,334,530 and 3,928,099 describe various ways of labelingpackaging materials, containers, stationary, blood bags and recordingpaper wherein sheet materials, e.g., microporous materials, containingadditives such as inorganic powder, printing inks, swellable agents,coloring agents, fillers etc. are used to create markings, e.g.,etching, scoring, printing, and writing, on the label. In general, theseprocesses require the use of high temperatures and/or the presence ofadditives within the microporous film in order to display the markingson the surface.

[0004] Labeling or printing information on transdermal systems has beena challenge. For example, use of printing inks, coloring agents,solvents and other additives necessary for printing may adverselyinteract with the active agents within the transdermal system. Toaddress these concerns, transdermal systems have been labeled using aprocess not requiring the use of inks. The backing layer of thetransdermal system is labelled by a thermal embossing process. Thepolyolefin face of the backing material is melted under pressure toreveal the label.

[0005] Notwithstanding some success, the existing technology forlabeling transdermal systems has not been entirely satisfactory. Theadditives in the backing layer and/or the adjacent layers can interactadversely with the active agents. Additionally the use of hightemperatures to label the transdermal systems may degrade variouscomponents of the transdermal systems or cause adhesive flow beyond theperimeter of the backing. These challenges would in turn affect thepotency and stability of the transdermal systems.

[0006] Further, the microporous films described previously are directlylaminated to a pressure sensitive adhesive to provide labels having goodadhesion. However, embossing microporous film after direct lamination toa pressure sensitive adhesive would be problematic. Embossing suchmicroporous films would result in a poorly resolved image due to theslow intrusion of the adhesive into the opaque film layer. The slowadhesive flow into the pores, accompanied by the crushing of the poresdue to embossing would render the film transparent. Further, theembossed image would be poorly resolved due to adhesive flow into thepores.

SUMMARY OF THE INVENTION

[0007] The present invention is directed to the aforementioned needs inthe art, and provides a transdermal system having a multilaminatebacking construction. In particular, the invention relates to a systemand method for labeling a transdermal drug delivery system, wherein theoutermost layer of the multilaminate backing layer contains anembossable and writeable material.

[0008] In one aspect, the invention relates to a multilaminate backingconstruction comprising

[0009] (a) an outer layer comprising an embossable and writablematerial;

[0010] (b) a tie layer, the tie layer disposed on the skin proximalsurface of the outer layer; and

[0011] (c) a base layer disposed on the skin proximal surface of the tielayer.

[0012] In another aspect, the multilaminate backing construction of theinvention comprises

[0013] (a) an outer layer comprising an embossable and writablematerial, wherein the outer layer is a microporous layer or amicrofibrullar layer;

[0014] (b) a tie layer comprising a secondary drug-containing reservoir,the tie layer disposed on the skin proximal surface of the outer layer;and

[0015] (c) a base layer disposed on the skin proximal surface of the tielayer.

[0016] In another aspect, the multilaminate backing construction of theinvention comprises

[0017] (a) an outer layer comprising an embossable and writablematerial, wherein the outer layer is a microporous layer or amicrofibrullar layer, wherein the outer layer is also a drug releaserate controlling means;

[0018] (b) a tie layer comprising an antagonist-containing reservoir,wherein the antagonist-containing reservoir is disposed on the skinproximal surface of the outer layer; and

[0019] (c) a base layer disposed on the skin proximal surface of the tielayer.

[0020] In another aspect, the multilaminate backing construction of theinvention comprises

[0021] (a) an outer layer comprising an embossable and writablematerial, wherein the outer layer is a microporous layer or amicrofibrullar layer;

[0022] (b) a tie layer comprising a secondary drug-containing reservoir,the reservoir comprising a beneficial agent, the secondarydrug-containing reservoir being disposed on the skin proximal surface ofthe outer layer; and

[0023] (c) a base layer disposed on the skin proximal surface of the tielayer, wherein the base layer is a drug release rate controlling means.

[0024] In another aspect, the multilaminate backing construction of theinvention comprises

[0025] (a) an outer layer comprising an embossable and writablematerial, wherein the outer layer is a microporous layer or amicrofibrullar layer;

[0026] (b) a multilaminate tie layer, the tie layer disposed on the skinproximal surface of the outer layer, wherein the tie layer may contain asecondary drug-containing reservoir; and

[0027] (c) a base layer disposed on the skin proximal surface of the tielayer.

[0028] In additional aspects, the multilaminate backing construction ofthe invention comprises a base layer impermeable to the drug within thedrug reservoir or the tie layer; wherein the base layer comprises amaterial which is insoluble in water, alcohol and organic solvents. Thebase layer may optionally be a multilaminate layer. In certainembodiments, the base layer may be a drug release rate controllingmeans, e.g., a drug release rate controlling membrane. The base layercomprises a polymer such as polyolefin laminates (Dow Chemical, Midland,Mich.), acrylonitrile copolymer films (BAREX, BP Chemicals, Koln,Germany), polyethylnapthalene (PEN), polyethylene terephthalate (PET),PET modified with adhesion improvement coatings such polyacrylates orpolyesters, polyimide, polyurethane, polyethylene, metallized films andglass coated films where these films can include ethylene copolymerssuch as ethylene-vinyl acetate copolymer (EVA), and combinationsthereof. In preferred embodiments, the base layer comprises polyester,such as PET, laminated to a polymer, such as polyurethane, polyethylene,and ethylene copolymers.

[0029] In preferred embodiments, the base layer is comprised of apolymeric material selected from the group consisting of apolyester-polyolefin material such as Scotchpak 9735 (PET-PE laminate,3M), Mediflex 1500 (PET-pigmented EVA laminate, Mylan Technologies),Mediflex 1200 (PET-EVA laminate, Mylan Technologies); Mediflex 1000 (atranslucent polyolefin film, Mylan Technologies), Medifilm 500 series(EVA membrane material, Mylan Technologies); polyethylenes such as lowdensity polyethylene (LDPE), medium density polyethylene (MDPE), highdensity polyethylene (HDPE), Kapton polyimide film, and other ethylenecopolymer films such as EMA, or EBA copolymer films.

[0030] In additional aspects, the multilaminate backing construction ofthe invention comprises an outer layer comprising an embossable andwriteable material. The outer surface can be scribed with a pen, and canbe embossed by applying pressure with an embossing roll before or afterlamination of the multilaminate backing construction to a pressuresensitive adhesive. The outer layer comprises a breathable materialcomprising, porous, microporous, microfibrullar, spun-bonded, spunlaced, track etched, rayon (synthetic textile fibers produced by forcinga cellulose solution through fine spinnerets and solidifying theresulting filaments), wood-pulp, spun laced polyester, coated paperproducts, and the like, and a combination thereof. In preferredembodiments, outer layer comprises low density polyethylene (LDPE)materials, medium density polyethylene (MDPE) materials or high densitypolyethylene (HDPE) materials, and the like. In preferred embodiments,the outer layer is a single HDPE layer. In additional preferredembodiments, the outer layer comprises a microporous layer selected fromthe group consisting of Solupor microporous UHDPE P01 film (Solupor™manufactured by DSM Desotech, the Netherlands), microporouspolypropylene, e.g. Celgard microporous PP 3401 film (Celgard™ film,Celgard, Inc., Charlotte, N.C.), RoTrac Polyester Capillary PoreMembranes (OYPHEN GmbH, Germany), spun laced polyester, polypropylene orpolyethylene.

[0031] In additional aspects, the multilaminate backing construction ofthe invention comprises a tie layer, wherein the tie layer may bemultilaminate. The tie layer is comprised of materials having a lowmelting point that flow easily at high temperatures to allow laminationto the outer layer. The tie layer may be formed from standard materialsas known in the art. For example, the tie layer is formed from ahydrophobic, a lipophilic and/or a non-polar polymeric material, suchas, ethyleneoctene copolymers such as ENGAGE 8407 (from Dupont-DowElastomers), ethylene-vinyl acetate copolymer (EVA), low densitypolyethylene (LDPE), medium density polyethylene (MDPE), non pressuresensitive formulation of styrenic block copolymer thermoplasticelastomers, and the like. In preferred embodiments, the tie layer isformed from ethyleneoctene copolymers, as described in greater detailbelow.

[0032] In additional aspects, the tie layer comprises a secondarydrug-containing reservoir. The secondary drug-containing reservoir maycontain a beneficial agent or an antagonist for the beneficial agent,wherein the antagonist is in a form that is not releasable through thebase layer. The skin distal surface of the drug reservoir is disposed onthe outer surface. The secondary drug-containing reservoir may be thesame size as the other layers of the backing construction or thesecondary drug-containing reservoir may be inset from the edge of thedie cut backing construction.

[0033] In certain embodiments, the secondary drug-containing reservoircomprises the drug dispersed within a polymer, wherein the drug issubstantially insoluble in the secondary drug-containing reservoirpolymer. In certain embodiments, the drug is dispersed in a matrixcomprising a material which substantially prevents release of the drug;or the drug is complexed with an ionic resin. In additional embodiments,the secondary drug-containing reservoir comprises the drug in amultiparticulate form, wherein each particle is individually coated witha material which substantially prevents release of the drug. Inadditional embodiments, the secondary drug-containing reservoircomprises beads coated with the drug, wherein the beads may be formedfrom glass or an inert or non-dissolvable polymer, and further whereinthe coated beads are optionally coated with or dispersed in materialwhich substantially prevents release of the drug. In preferredembodiments, the drug is an opioid antagonist selected from the groupconsisting of naltrexone, methylnaltrexone, naloxone, nalbuphine,nalorphine, nalorphine dinicotinate, nalmefene, nadide, levallorphan,cyclozocine and pharmaceutically acceptable salts thereof. In preferredembodiments, the antagonist is present as a salt, preferably as ahydrochloride salt of an antagonist base.

[0034] These and other embodiments of the present invention will readilyoccur to those of ordinary skill in the art in view of the disclosureherein.

BRIEF DESCRIPTION OF THE FIGURES

[0035]FIG. 1 illustrates a cross-section through a schematic,perspective view of one embodiment of multilaminate backing constructionaccording to this invention.

[0036]FIG. 2 illustrates a cross-section through a schematic,perspective view of another embodiment of multilaminate backingconstruction according to this invention.

DETAILED DESCRIPTION OF THE INVENTION

[0037] Overview:

[0038] The present invention is directed to a transdermal system havinga multilaminate backing construction wherein the outermost layer of themultilaminate backing construction can be embossed and be written uponwith a pen or pencil. In particular, the outermost layer of themultilaminate backing construction of the present invention contains anembossable and writable material such as a microporous or microfibrillarfilm, which is laminated via a tie layer to a base layer.

[0039] Definitions:

[0040] In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

[0041] The singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a polymer” includes a single polymer as well as a mixtureof two or more different polymers, reference to “a permeation enhancer”includes a single permeation enhancer as well as two or more differentpermeation enhancer in combination, and the like.

[0042] As used herein, the term “drug release controlling means” refersto a means to control/regulate the release of a drug from the secondarydrug-containing reservoir.

[0043] As used herein, the terms “drug” and “active agent” are usedinterchangeably and are to be construed in the broadest sense to meanany material which is intended to produce some biological, beneficial,therapeutic, or other intended effect, such as permeation enhancement,an antagonist, on the organism to which it is applied. For example, thedrug may be a beneficial agent or an antagonist of the beneficial agent.

MODES FOR CARRYING OUT THE INVENTION

[0044] The present invention provides a multilaminate backingconstruction for a transdermal drug delivery system, the outermost layerof the multilaminate backing construction having an embossable andwritable material.

[0045] Referring now to FIG. 1, a preferred embodiment of themultilaminate backing construction 1 according to this inventioncomprises an outer layer 2, a tie layer 3 wherein the skin distalsurface of the tie layer is disposed on the outer layer 2, and a baselayer 4 wherein the tie layer 3 is disposed on the skin distal surfaceof the base layer 4. In certain embodiments of the backing construction1 of the invention, the tie layer 3 is a secondary drug-containingreservoir disposed on the skin proximal surface of the outer layer 2,and the base layer 4 is disposed on the skin proximal surface of thesecondary drug-containing reservoir. The secondary drug-containingreservoir may contain a beneficial agent or an antagonist for abeneficial agent. In certain embodiments of the backing construction 1of the invention, wherein the secondary drug-containing reservoircontains a beneficial agent, the base layer 4 is a drug rate controllingmeans disposed on the skin proximal surface of the secondarydrug-containing reservoir. In alternative embodiments of the backingconstruction 1 of the invention, the secondary drug-containing reservoircontains an antagonist of a beneficial agent, and preferably, the outerlayer also functions as an antagonist release rate controlling means.

[0046] Referring now to FIG. 2 a preferred embodiment of themultilaminate backing construction 11 according to this inventioncomprises an outer layer 12, a multilaminate tie layer 13 and a baselayer 14. The tie layer comprises a first layer 16 disposed on the skinproximal surface of the outer layer 12; a second layer 17 disposed onthe skin proximal surface of the first layer 16; a third layer 18disposed on the skin proximal surface of the second layer 17; and asecondary drug-containing reservoir 15. The base layer 14 is configuredto provide a central volume which contains the secondary drug-containingreservoir 15 in the form of a gel having dissolved or suspended drugtherein. In preferred embodiments, the first layer 16 is an EVA or LDPElayer, the second layer 17 is a PET layer, the third layer 18 is an EVA,LDPE or a polyurethane layer; and the base layer 14 is a drug releaserate controlling means.

[0047] The outer layer 2, 12, of the multilaminate backing constructionof the invention comprises an embossable and writeable material. Theouter surface can be scribed with a pen, and can be embossed by applyingpressure with an embossing roll before or after lamination of themultilaminate backing construction to a pressure sensitive adhesive. Theouter layer comprises a breathable material comprising, porous,microporous, microfibrullar, spun-bonded, spun laced, track etched,rayon (synthetic textile fibers produced by forcing a cellulose solutionthrough fine spinnerets and solidifying the resulting filaments),wood-pulp, spun laced polyester, coated paper products, and the like,and a combination thereof. In preferred embodiments, outer layercomprises low density polyethylene (LDPE) materials, medium densitypolyethylene (MDPE) materials or high density polyethylene (HDPE)materials, and the like. In preferred embodiments, the releasecontrolling means is a single LDPE layer. In additional preferredembodiments, the outer layer comprises a microporous layer selected fromthe group consisting of Solupor microporous UHDPE P01 film (Solupor™manufactured by DSM Desotech, the Netherlands), microporouspolypropylene, e.g. Celgard microporous PP 3401 film (Celgard™ filmmanufactured by Celgard, Inc., Charlotte, N.C.), RoTrac PolyesterCapillary Pore Membranes (OYPHEN GmbH, Switzerland), spun lacedpolyester, polypropylene or polyethylene. The outer layer is free of anyadditives and is not directly laminated to a pressure sensitiveadhesive. Alternatively, the outer layer can be coated with low levelsof surfactants, for example, pluronic polyethylene oxide-polypropyleneoxide block copolymers and the like, to provide further control over therate of drug release from the underlying tie layer.

[0048] The outer layer 2,12, has a thickness of about 0.012 mm (0.5 mil)to about 0.125 mm (5 mil); preferably 0.025 mm (1 mil) to about 0.1 mm(4 mil); more preferably 0.0375 mm (1.5 mil) to about 0.0875 mm (3.5mil); and even more preferably 0.05 mm (2 mil) to about 0.0625 mm (2.5mil).

[0049] The multilaminate backing construction according to the inventioncomprises a tie layer 3, 13, wherein the tie layer may be multilaminate.The tie layer is comprised of materials having a low melting point thatflow easily at high temperatures to allow lamination to the outer layer2, 12, such materials excluding pressure sensitive adhesives and HDPE.HDPE has a very high melting point and its use in the outer layer wouldrender the embossable film prematurely clear due to high laminatingtemperatures and coincidental melting of the outer layer. Incorporationof pressure sensitive materials in the outer layer would result in flowof the adhesive into the pores, which would result in the embossablefilm prematurely turning clear. In certain embodiments, the tie layercomprises a secondary drug-containing reservoir. The secondarydrug-containing reservoir may contain a beneficial agent or anantagonist for the beneficial agent. In certain embodiments, when thesecondary drug-containing reservoir contains an antagonist, the outerlayer also functions as a drug release rate controlling means. Incertain embodiments, when the second drug-containing reservoir containsa beneficial agent, the base layer 4 is a drug release rate controllingmeans is disposed on the skin proximal surface of the secondarydrug-containing reservoir. The secondary drug-containing reservoir maybe THE same size as the other layers of the backing construction or thesecondary drug-containing reservoir may be inset from the edge of thedie cut backing construction. The tie layer may be formed from standardmaterials as known in the art. In particular, the tie layer 3, 13, isformed from low melting materials that flow easily at high temperaturesand exclude pressure sensitive adhesives and HDPE. For example, the tielayer is formed from a hydrophobic, a lipophilic and/or a non-polarpolymeric material, such as, ethyleneoctene copolymers such as ENGAGE8407 (from Dupont-Dow Elastomers), ethylene-vinyl acetate copolymer(EVA), low density polyethylene (LDPE), medium density polyethylene(MDPE), styrenic block copolymer thermoplastic elastomers, PET,polyurethanes, and the like. In preferred embodiments, the tie layer isformed from ethyleneoctene copolymers, as described in greater detailbelow.

[0050] In certain embodiments wherein the tie layer contains a secondarydrug-containing reservoir, particularly an antagonist-containingreservoir, the antagonist is dispersed in a matrix comprising apolymeric material which substantially prevents release of theantagonist, preferably a thermoformable material; or the antagonist iscomplexed with an ionic resin. In additional embodiments, theantagonist-containing reservoir comprises the antagonist in amultiparticulate form, wherein each particle is individually coated witha polymeric material which substantially prevents release of theantagonist, wherein the polymeric material is preferably athermoformable material. In additional embodiments, theantagonist-containing reservoir comprises beads coated with theantagonist, wherein the beads may be formed from glass or an inert ornon-dissolvable polymer, and further wherein the coated beads areoptionally coated with or dispersed in a polymeric material whichsubstantially prevents release of the antagonist, wherein the polymericmaterial is preferably a thermoformable material. Examples of antagonistinclude, but are not limited to, naltrexone, methylnaltrexone, naloxone,nalbuphine, nalorphine, nalorphine dinicotinate, nalmefene, nadide,levallorphan, cyclozocine and the like, and pharmaceutically acceptablesalts thereof. Preferably, the antagonist is present as a salt.

[0051] As discussed above, the antagonist-containing reservoir comprisesthe antagonist dispersed within a polymer. Preferably, the antagonist isdispersed in a matrix comprising a thermoformable material whichsubstantially prevents release of the antagonist. Alternatively, theantagonist is present in a multiparticulate form, wherein each particleis individually coated with a polymeric material which substantiallyprevents release of the antagonist. Preferably, the polymeric materialwhich substantially prevents release of the antagonist ishydrophobic—i.e., substantially prevents release of the antagonistduring normal use, minimizes the amount of antagonist duringincidental/casual exposure to solvents (moisture e.g., sweat, during ashower), and upon ingestion or immersion in a solvent, releases theantagonist in abuse limiting amounts. Preferably, the polymeric materialhas a low melting point to allow processing of the antagonist in solidphase and to prevent degradation of the antagonist. Examples of apolymeric material which substantially prevents release of theantagonist include, but are not limited to, polyethylene, polyoctene,polyvinyl acetate, polymethyl acrylate, polymethyl acrylate, polyethylacrylate, polystyrene polymers and copolymers and mixtures thereof;polystyrene copolymers such as styrenic block copolymers (SIS, SBS,SEBS), ethylene copolymers such as polyethyleneoctene copolymers,ethylene-vinyl acetate copolymer (EVA), ethylenemethyl acrylatecopolymers (EMA), ethylene-acrylic acid copolymer,ethylene-ethylacrylate copolymer, and the like, and combinationsthereof.

[0052] In additional embodiments, the antagonist is complexed with anionic resin. Examples of ionic resins include, but are not limited tosulfonated polystyrene resins, and the like. Preferably the resincontains a sulfonic acid functionality which when neutralized with theantagonist base forms the sulfonate salt of the antagonist.

[0053] In additional embodiments, the antagonist-containing reservoircomprises beads coated with the antagonist, wherein the spheres or beadsmay be formed from glass, metals or an inert or non-dissolvable polymer,and further wherein the coated beads are optionally coated with ordispersed in a polymeric material which substantially prevents releaseof the antagonist, as described above. The beads may be in any shape,size or form, but are preferably small sized, preferably less than 10microns. Examples of an inert or non-dissolvable polymer include, butare not limited to polymethylmethacrylate, polycarbonate andpolystyrene.

[0054] In certain embodiments wherein the tie layer contains a secondarydrug-containing reservoir, the secondary drug-containing reservoir isdisposed on the skin proximal surface of the outer layer 2 and the skindistal surface of the base layer 4. The secondary drug-containingreservoir may be formed from standard materials as known in the art. Forexample, the secondary drug-containing reservoir is formed from ahydrophobic and/or lipophilic polymeric material, such as, hydrophobicpolyurethane, ethylene-vinyl acetate copolymer (EVA) and the like.

[0055] In preferred embodiments, when the drug is a beneficial agent,the secondary drug-containing reservoir comprises about 5 to about 35 wt% of the drug; more preferably about 10 to about 35 wt % of the drug;and even more preferably about 15 to about 30 wt % of the drug. Examplesof beneficial agent include, but are no limited to, fentanyl,sufentanil, risperidone, gallantamine, norelgestromin, testosterone,estradiol, nicotine, methylphenidate, fenoldopam, and the like.Preferably, the material forming the secondary drug-containing reservoirhas a solubility for the drug of about 5 wt % to about 40 wt % of thetotal polymer composition; more preferably about 10 wt % to about 35 wt%; and even more preferably about 15 wt % to about 30 wt % of the totalpolymer composition.

[0056] In additional preferred embodiments, the drug is an antagonist,preferably the antagonist is in the salt form and the preferredantagonists are naltrexone, methyinaltrexone, naloxone, nalbuphine,nalorphine, nalorphine dinicotinate, nalmefene, nadide, levallorphan andcyclozocine. When the drug is an antagonist of a beneficial agent, thesecondary drug-containing reservoir comprises about 20 to about 70 wt %of the drug; more preferably about 40 to about 65 wt % of the drug; andeven more preferably about 50 to about 60 wt % of the drug. Preferably,the material forming the secondary drugcontaining reservoir 5 has asolubility for the drug of about 0 wt % to about 1 wt % of the totalpolymer composition; more preferably about 0 wt % to about 0.8 wt %; andeven more preferably about 0 wt % to about 0.5 wt % of the total polymercomposition.

[0057] The tie layer 3, 13,including the secondary drug-containingreservoir, has a thickness of about 0.0125 mm (0.5 mil) to about 0.1 mm(4 mil); preferably about 0.015 mm (0.6 mil) to about 0.0875 mm (3.5mil); more preferably 0.025 mm (1 mil) to about 0.08 mm (3.3 mil); andeven more preferably about 0.02 mm (1.6 mil) to about 0.075 (3 mil).

[0058] In additional embodiments, the secondary drug-containingreservoir may optionally contain additional components such as,permeation enhancers, stabilizers, diluents, antioxidants, excipients,gelling agents, anti-irritants, vasoconstrictors and other materials asare generally known to the transdermal art.

[0059] Examples of permeation enhancers include, but are not limited to,fatty acid esters of glycerin, such as capric, caprylic, dodecyl, oleicacids; fatty acid esters of isosorbide, sucrose, polyethylene glycol;caproyl lactylic acid; laureth-2; laureth-2 acetate; laureth-2 benzoate;laureth-3 carboxylic acid; laureth-4; laureth-5 carboxylic acid;oleth-2; glyceryl pyroglutamate oleate; glyceryl oleate; N-lauroylsarcosine; N-myristoyl sarcosine; N-octyl-2 pyrrolidone;lauraminopropionic acid; polypropylene glycol-4-laureth-2; polypropyleneglycol-4-laureth-5 dimethyl lauramide; lauramide diethanolamine (DEA).Preferred enhancers include, but are not limited to, laurylpyroglutamate (LP), glyceryl monolaurate (GML), glyceryl monocaprylate,glyceryl monocaprate, glyceryl monooleate (GMO), and sorbitanmonolaurate. Additional examples of suitable permeation enhancers aredescribed, for example, in U.S. Pat. Nos. 5,785,991; 5,843,468;5,882,676; and 6,004,578.

[0060] The multilaminate backing construction according to thisinvention comprises a base layer 4, 14, wherein the tie layer 3, 13, isdisposed on the skin distal surface of the base layer 4, 14. The baselayer 4, 14, may be multilaminate. The base layer 4 comprises a polymersuch as polyolefin laminates (Dow Chemical, Midlane, Mich.),acrylonitrile copolymer films (BAREX, BP Chemicals, Koln, Germany),polyethylnapthalene (PEN), polyethylene terephthalate (PET), polyimide,polyurethane, polyethylene, metallized films and glass coated filmswhere these films can include ethylene copolymers such as ethylene-vinylacetate copolymer (EVA), and combinations thereof. In preferredembodiments, the base layer comprises a polyester such as PET laminatedto a polymer such as polyurethane, polyethylene, and ethylenecopolymers. In certain embodiments, the base layer may be a drug ratecontrolling means, as described in greater detail hereinafter. Incertain embodiments wherein the secondary drug-containing reservoircontains an antagonist, the base layer 4 is impermeable to theantagonist within the secondary drug-containing reservoir; the baselayer comprising a material which is insoluble in water, alcohol andorganic solvents.

[0061] In preferred embodiments, the base layer is comprised of apolymeric material selected from the group consisting of apolyester-polyolefin material such as Scotchpak 9735 (PET-PE laminate,3M), Mediflex 1500 (PET-pigmented EVA laminate, Mylan Technologies,Saint Albans, Vt.), Mediflex 1200 (PET-EVA laminate, Mylan Technologies,Saint Albans, Vt.); Mediflex 1000 (a translucent polyolefin film, MylanTechnologies, Saint Albans, Vt.), Medifilm 500 series (EVA membranematerial, Mylan Technologies, Saint Albans, Vt.); polyethylenes such aslow density polyethylene (LDPE), medium density polyethylene (MDPE),high density polyethylene (HDPE), ethylene methyl acrylate copolymer(EMA), ethylene ethyl acrylate copolymer (EEA), or ethylene butylacrylate copolymer (EBA) copolymers. The base layer has a thickness ofabout 0.01 mm (0.4 mil) to about 0.125 mm (5 mil); preferably 0.025 mm(1 mil) to about 0.1 mm (4 mil); more preferably 0.0625 mm (1.5 mil) toabout 0.0875 mm (3.5 mil); and even more preferably 0.025 mm (1 mil) toabout 0.05 mm (2 mil).

[0062] The multilaminate backing construction comprises a drug releaserate controlling means, preferably within the outer layer or within thebase layer. In certain embodiments, when the secondary drug-containingreservoir is an antagonist-containing reservoir, the outer layer 2, 12,also functions as a drug release rate controlling means disposed on theskin distal surface of the secondary drug-containing reservoir. Inalternative embodiments, when the secondary drug-containing reservoircontains a beneficial agent, the base layer 4, 14, is a drug releaserate controlling means disposed on the skin proximal surface of thesecondary drug-containing reservoir. In preferred embodiments, the tielayer comprises an antagonist-containing reservoir, and the outer layeris a drug release controlling means.

[0063] The rate controlling means is made of a polymeric material suchas ethylene-vinyl acetate (EVA), polyvinyl chloride (PVC),ethylene-ethyl acrylate copolymer, ethylene butylacrylate copolymer,polyisobutylene (PIB), polyethylene (PE) such as low densitypolyethylene (LDPE), medium density polyethylene (MDPE), high densitypolyethylene (HDPE), and the like, and a combination thereof; thepolymeric materials may be plasticized. In preferred embodiments, thebase layer is a drug release rate controlling means and is adhered tothe skin with an acrylic, silicone, polyisobutylene (PIB) or otherpressure sensitive adhesive material. The rate controlling means has athickness of about 0.012 mm (0.5 mil) to about 0.125 mm (5 mil);preferably 0.025 mm (0.6 mil) to about 0.1 mm (4 mil); more preferably0.0625 mm (0.8 mil) to about 0.0875 mm (3.5 mil).

[0064] The multilaminate backing construction can be processed with lessstretching under web tension because of the less extensible outer layer,preferably the Solupor layer, which also provides a surface forembossing and writing.

[0065] The transdermal devices are manufactured according to knownmethodology. In general, the transdermal device according to thisinvention comprises a backing construction 1, 11, a primarydrug-containing reservoir disposed on the backing construction, whereinat least the skin contacting surface of the primary drug-containingreservoir is adhesive, and a peelable protective layer. Themultilaminate backing construction is laminated via a pressure sensitiveadhesive to a primary drug-containing reservoir. The primarydrug-containing reservoir is typically formed from a pharmaceuticallyacceptable pressure sensitive adhesive but, in some cases, can be formedfrom a non-adhesive material. If the primary drug-containing reservoiris formed from a material that does not have adequate adhesiveproperties, the primary drug-containing reservoir may be formulated witha thin adhesive coating. The primary drug-containing reservoirintermediate is optionally laminated to a drug release-rate controllingmembrane disposed between the primary drug-containing drug reservoir andthe peelable protective layer. In subsequent operations, individualtransdermal devices are die-cut, separated and unit-packaged usingsuitable pouchstock. Transdermal devices are cartoned using conventionalequipment. The resulting transdermal delivery system provides arate-controlled drug delivery device having embossing and writingcapabilities.

[0066] Transdermal drug delivery systems having the multilaminatebacking construction containing an antagonist-containing reservoirwithin the tie layer, when used in combination with opioid-deliveringtransdermal formulations, provide a deterrence to drug abusersattempting to misuse the systems, while at the same time, enableembossed labeling or scribing with a pen.

[0067] The multilaminate backing construction is embossed by applicationof pressure without the application of high temperatures, and withoutmelting the outer layer. Simply applying pressure without increasing thetemperature is sufficient to provide a very striking visual graphic. Themethod of labeling a transdermal system using the multilaminate backingconstruction of the invention eliminates the need for solvent-based inkswhen printing transdermal systems by a heat-free embossing technique.Additionally, the method of the invention eliminates adversedrug-additive interactions, improving stability, thermal sensitivity,therapeutic effects,shelf-life and ease of manufacture of a transdermaldrug delivery system.

[0068] Additionally, the multilaminate backing construction of theinvention is writable, allowing physicians, nurses, or users to writedirectly on the backing with a pen without the ink smearing. Thisfeature is important in many clinical settings because physicians andnurses need to indicate on multiple-day transdermal systems whenreplacement is required. If not replaced at the appropriate time,sub-therapeutic quantities of drug may be delivered as the drug contentin the system depletes.

[0069] Further, when the multilaminate backing construction is laminatedto a primary drug-containing adhesive matrix, the drug cannot penetratethrough the multilaminate backing construction into the heat seal layerof the pouch material due to the microporous/microfibrous nature of theouter layer.

[0070] In additional embodiments, the multilaminate backing constructionis laminated to a pressure sensitive adhesive, enabling bonding to anymedical device such as a blood bag, IV bag, or form-fill-sealtransdermal patch, e.g. Duragesic® transdermal fentanyl delivery system.

[0071] A wide variety of materials which can be used for fabricating thevarious layers of the multilaminate backing construction according tothis invention have been described above. This invention thereforecontemplates the use of materials other than those specificallydisclosed herein, including those which may hereafter become known tothe art to be capable of performing the necessary functions.

[0072] Methods of Manufacture

[0073] The multilaminate backing construction of the invention aremanufactured as follows. The drug-containing reservoirs are manufacturedaccording to known methodology, as described in greater detail below.

[0074] Drug-Containing Reservoir

[0075] The secondary drug-containing reservoir can be formed by dryblending a drug, with a polymeric material, preferable a thermoformablematerial, at high shear and temperature using equipment such as sigmablade mixers or extruders, either batch-wise or continuously. Theextrudate is calendered to the desired thickness between release liners,followed by lamination at elevated temperature to a barrier film and/oran analgesic rate controlling means. Parameters such as drug loading,drug-containing reservoir thickness, membrane selection for the ratecontrolling means, and surfactant modification of the rate controllingmeans can be varied to achieve the targeted release rate of drug, asillustrated in the Examples hereinafter. In preferred embodiments,surfactants are coated onto membrane materials forming the ratecontrolling means using techniques such as dip-coating, gravure coating,and the like.

[0076] In alternative embodiments, the secondary drug-containingreservoirs are manufactured according to known methodology as follows. Asolution of the polymeric reservoir material, as described above, isadded to a double planetary mixer, followed by addition of desiredamounts of the drug, and optionally, a permeation enhancer. Preferably,the polymeric secondary drug-containing reservoir material issolubilized in an organic solvent, e.g., ethanol, ethyl acetate, hexane,and the like. The mixer is then closed and activated for a period oftime to achieve acceptable uniformity of the ingredients. The mixer isattached by means of connectors to a suitable casting die located at oneend of a casting/film drying line. The mixer is pressurized usingnitrogen to feed solution to the casting die. Solution is cast as a wetfilm onto a moving siliconized polyester web. The web is drawn throughthe lines and a series of ovens are used to evaporate the castingsolvent to acceptable residual limits. The dried secondarydrug-containing reservoir film is then laminated to a selected baselayer and the laminate is wound onto the take-up rolls. In anotherprocess, the secondary drug-containing reservoir can be formed usingdry-blending and thermal film-forming using equipment known in the art.Preferably, the materials are dry blended and extruded using a slot diefollowed by calendering to an appropriate thickness. Parameters such asdrug loading, secondary drug-containing reservoir thickness, drugselections, material selections and manufacturing process can be variedfor preparing drug-containing reservoirs of the current invention, asillustrated in the Examples hereinafter.

[0077] The primary drug-containing reservoir is manufactured asdescribed above using known materials and according to known procedures.

[0078] Multilaminate Backing Construction

[0079] In general, the multilaminate backing construction ismanufactured as follows. For example, as illustrated in FIG. 1, the tielayer is laminated to the base layer, followed by lamination of theouter layer on the surface of the tie layer distal to the base layer atelevated temperature and pressure. Alternatively, both laminations couldbe conducted in a single operation by extruding the tie layer at therequired width and thickness directly between the outer layer and thebase layer prior to lamination. In general, the lamination is performedat a temperature ranging from about 70° C. to about 120° C., and apressure ranging from 50 psi to about 120 psi, at the rate ranging fromabout 2 fpm to about 20 fpm.

[0080] In an alternative embodiment, wherein the tie layer comprises asecondary drug-containing reservoir, the multilaminate backingconstruction, is manufactured by laminating sequentially orsimultaneously the secondary drug-containing reservoir layer to the baselayer and to the outer layer under lamination conditions as describedabove. The secondary drug-containing reservoir is manufactured asdescribed earlier.

[0081] In another embodiment of the multilaminate backing construction,as illustrated in FIG. 2, the tie layer is a multilaminate layercontaining an outermost first layer 16 (EVA/LDPE layer) on the skinproximal surface of the outer layer, laminated to a second layer 17 (PETlayer) disposed on the skin proximal surface of the first layer 16, thebi-layer is further laminated to a third layer 18 (EVA/LDPE/polyurethanelayer) disposed on the skin proximal surface of the second layer 17, anda form fill type of a secondary drug-containing reservoir 15. The baselayer 14, e.g. a drug release rate controlling means, is configured toprovide a central volume which contains the secondary drug-containingreservoir 15 in the form of a gel having dissolved or suspended drugtherein.

[0082] Experimental

[0083] Below are examples of specific embodiments for carrying out thepresent invention. The examples are offered for illustrative purposesonly, and are not intended to limit the scope of the present inventionin any way.

[0084] Efforts have been made to ensure accuracy with respect to numbersused (e.g., amounts, temperatures, etc.), but some experimental errorand deviation should, of course, be allowed for.

[0085] Specific examples of various multilaminate backing constructionof the invention will be described in the examples set for hereinafter.In the following examples all percentages are by weight unless notedotherwise.

EXAMPLE 1

[0086] A polyester-polyolefin transdermal backing material such asScotchpak 9735 (PET-PE laminate, 3M, Cottage Grove, Minn.), Mediflex1500 (PET-pigmented EVA laminate, Mylan Technologies, Saint Albans,Vt.), or Mediflex 1200 (PET-EVA laminate, Mylan Technologies) arelaminated to Solupor microfibrous UHMW-HDPE P01 film (DSM Solutech,Heerlen, the Netherlands) at elevated temperature and pressure. Thetemperature required for the lamination is above the melting point ofthe polyolefin layer of the backing, usually above 100° C. The resultingmultilaminate is used as a transdermal backing, the Solupor surface ofwhich can be scribed with a pen, and which can be embossed by applyingpressure with an embossing roll before or after lamination to a pressuresensitive adhesive.

EXAMPLE 2

[0087] Mediflex 1200, a polyester—EVA laminate, is bonded to a Solupormicrofibrous UHMW-HDPE film via a tie layer. The tie layer contains anENGAGE 8407 ethylene-octene copolymer (Dupont-Dow Elastomers, DSMSolutech's) containing a naltrexone hydrochloride dispersion. Adequatebonding is achieved by performing a hot lamination step at 90 psi, 5fpm, and 100° C. The resulting multilayered construction is laminated toa fentanyl-containing adhesive reservoir. The resulting construction isembossed for identification, can be written upon with a ballpoint pen,and contains the antagonist, naltrexone hydrochloride, to preventfentanyl abuse.

EXAMPLE 3

[0088] A multilaminate backing construction using Celgard microporous PP3401 film (Celgard Microporous Membrane) is prepared, as described inExample 1 above.

EXAMPLE 4

[0089] A multilaminate backing construction using Rotrac Capillary PoreMembrane (Oxyphen, Zug, Switzerland) is prepared, as described inExample 1 above.

EXAMPLE 5

[0090] A multilaminate backing construction using Celgard microporous PP3401 film is prepared, as described in Example 2 above.

EXAMPLE 6

[0091] A multilaminate backing construction using Rotrac Capillary PoreMembrane (Oxyphen, Zug, Switzerland)microporous polyester is prepared,as described in Example 2 above.

EXAMPLE 7

[0092] A translucent polyolefin film, Mediflex 1000 (Mylan Technologies,Saint Albans, Vt.), is laminated to the Solupor microfibrous film P01via a low melting Engage 8407 ethylene-octene copolymer. The conditionsrequired for the lamination are 80° C., 90 psi, and 3 fpm. The resultingtransdermal backing material can be processed with less stretching underweb tension because of the less extensible Solupor layer, which alsoprovides a surface for embossing and writing. Further, when this backingmaterial is laminated to a primary drug-containing adhesive matrix, drugcannot penetrate through the multi-layered backing into the heat seallayer of the pouch material because of the microfibrous nature of theSolupor layer.

EXAMPLE 8

[0093] The procedure outlined in Example 7 is followed except an EVAfilm is substituted for the LDPE film. The resulting constructionprovides the benefits outlined in example 7 with the added benefit ofproviding an additional drug reservoir in the EVA backing layer. Drugincorporation into the EVA film is achieved during its extrusion orthrough the slow diffusion of drug into the EVA after lamination to anactive drug-pressure sensitive adhesive reservoir.

EXAMPLE 9

[0094] A LDPE or EVA membrane material such as the Medifilm 500 seriesfrom Mylan Technologies, is laminated to a polyolefin drug reservoirconsisting of an EVA-40 drug dispersion, which is, in turn, laminated tothe Solupor P01 film at 70° C., 50 psi, and 3 fpm on hot laminationequipment. The resulting multi-layered construction, after lamination toa pressure sensitive adhesive, provides rate-controlled drug delivery,embossing, and writing capabilities.

EXAMPLE 10

[0095] Any of the multilayered constructions described in Examples 1-9are laminated to a pressure sensitive adhesive, enabling bonding to anymedical device such as a blood bag, IV bag, or form-fill-sealtransdermal patch such as Duragesic transdermal fentanyl deliverysystem.

[0096] The above-described exemplary embodiments are intended to beillustrative in all respects, rather than restrictive, of the presentinvention. Thus the present invention is capable of many variations indetailed implementation that can be derived from the descriptioncontained herein by a person skilled in the art. All such variations andmodifications are considered to be within the scope and spirit of thepresent invention.

1. A multilaminate backing construction comprising: (a) an outer layercomprising an embossable and writable material; (b) a tie layer, the tielayer disposed on the skin proximal surface of the outer layer; and (c)a base layer disposed on the skin proximal surface of the tie layer. 2.The multilaminate backing construction of claim 1 wherein the outerlayer comprises a breathable material.
 3. The multilaminate backingconstruction of claim 2 wherein the outer layer comprises a breathablematerial comprising, porous, microporous, microfibrullar, spun-bonded,spun laced, track etched, rayon, wood-pulp, spun laced polyester, orcoated paper products and combinations thereof.
 4. The multilaminatebacking construction of claim 3 wherein the outer layer comprises amaterial selected from the group consisting of low density polyethylene(LDPE), medium density polyethylene (MDPE), high density polyethylene(HDPE), ultra high density polyethylene (UHDPE), polypropylene,polyester, and polyethylene.
 5. The multilaminate backing constructionof claim 1 the tie layer comprises a hydrophobic, a lipophilic or anon-polar polymeric material and combinations thereof.
 6. Themultilaminate backing construction of claim 5 wherein the tie layercomprises ethyleneoctene copolymers, ethylene-vinyl acetate copolymer(EVA), low density polyethylene (LDPE), medium density polyethylene(MDPE), non pressures sensitive formulation of styrenic block copolymeror thermoplastic elastomers, and combinations thereof.
 7. Amultilaminate backing construction comprising: (a) an outer layercomprising an embossable and writable material, wherein the outer layeris a microporous layer or a microfibrullar layer; (b) a tie layercomprising a secondary drug-containing reservoir, the tie layer disposedon the skin proximal surface of the outer layer; and (c) a base layerdisposed on the skin proximal surface of the tie layer.
 8. Amultilaminate backing construction comprising: (a) an outer layercomprising an embossable and writable material, wherein the outer layeris a microporous layer or a microfibrullar layer; (b) a tie layercomprising an antagonist-containing reservoir, wherein theantagonist-containing reservoir is disposed on the skin proximal surfaceof the outer layer; and (c) a base layer disposed on the skin proximalsurface of the tie layer.
 9. The multilaminate backing construction ofclaim 8 wherein the antagonist is in a form that is not releasablethrough the base layer and the outer layer is an antagonist release ratecontrolling means.
 10. The multilaminate backing construction of claim 9wherein the outer layer is coated with surfactants.
 11. Themultilaminate backing construction of claim 8 wherein the base layer isimpermeable to the antagonist within the antagonist-containingreservoir.
 12. A multilaminate backing construction comprising: (a) anouter layer comprising an embossable and writable material, wherein theouter layer is a microporous layer or a microfibrullar layer; (b) a tielayer comprising a secondary drug-containing reservoir, the reservoircomprising a beneficial agent, the secondary drug-containing reservoirbeing disposed on the skin proximal surface of the outer layer; and (c)a base layer disposed on the skin proximal surface of the tie layer,wherein the base layer is a drug release rate controlling means.
 13. Amultilaminate backing construction comprising: (a) an outer layercomprising an embossable and writable material, wherein the outer layeris a microporous layer or a microfibrullar layer; (b) a multilaminatetie layer, the tie layer disposed on the skin proximal surface of theouter layer; and (c) a base layer disposed on the skin proximal surfaceof the tie layer.
 14. The multilaminate backing construction of claim 13wherein the tie layer comprises a secondary drug-containing reservoir.15. The multilaminate backing construction of claim 13 wherein themultilaminate tie layer comprises: (i) a first layer disposed on theskin proximal surface of the outer layer; (ii) a second layer disposedon the skin proximal surface of the first layer; (iii) a third layerdisposed on the skin proximal surface of the second layer; and (iv) asecondary drug-containing reservoir.
 16. The multilaminate backingconstruction of claim 15 wherein the first layer is ethylene-vinylacetate copolymer (EVA) or low density polyethylene (LDPE) layer; thesecond layer is a polyethylene terephthalate (PET) layer; the thirdlayer is ethylene-vinyl acetate copolymer (EVA); low densitypolyethylene (LDPE) layer, or a polyurethane layer.
 17. Themultilaminate backing construction of claim 14 or claim 15 wherein thesecondary drug-containing reservoir comprises a beneficial agent and thebase layer is a drug release rate controlling means.